Large scale synthesis of pateamine A intermediates in route to designed derivatives for putative cellular receptor isolation and receptor/ligand studies: conformational studies of pateamine A

Abstract

Molecules that inhibit the immune response by blocking a specific signaling pathway involved in T-cell activation have proven to be useful biochemical tools. Pateamine A, a potent immunosuppressant isolated from the Mycale sp. sponge, specifically inhibits an intercellular step of the T-cell receptor signal transduction pathway leading to 1L-2 production. The large scale synthesis of pateamine A intermediates was therefore undertaken in order to generate substantial quantities of the natural product and synthetic intermediates to be used in preparation of derivatives useful for putative cellular receptor isolation and structure activity studies. A 2,4-DNB pateamine A hybrid has been successfully synthesized for use in cellular receptor isolation studies. Molecular mechanics studies using Cerius II software were performed and these studies in conjunction with preliminary structure-activity data led to a binding/scaffolding hypothesis. Based on this hypothesis, several simplified pateamine A derivatives were designed and synthetic studies toward these derivatives were initiated.